Diagnostic value of an increase in central venous pressure during SBT for prediction of weaning failure in mechanically ventilated patients: A cross‐sectional study

Abstract Background Timely and successful extubation is an essential step forward in clinical practice to minimize complications of mechanical ventilation and unsuccessful weaning processes. Thus, research into predictive factors of weaning outcome to optimize spontaneous breathing trial (SBT) precision before extubation is critical in intensive care practices. In this study, we aimed to investigate the predictive factors of the weaning outcome before and during SBT in mechanically ventilated patients. Methods In this cross‐sectional study, 159 mechanically ventilated patients who were eligible for SBT were enrolled. Of these patients, 140 had successful extubation, whereas the remainder failed. Each patient's PaCO2 and PaO2 levels, respiratory rate (RR), SpO2, mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) values at the start of SBT, 3 min later, and at the end of SBT were measured. These values, along with the patients' clinical characteristics, were then investigated to determine if there was any correlation between these variables and the weaning outcome. Results Our analysis revealed that increase in CVP, independent of hemoglobin (Hb) concentration, PaO2, SpO2, duration of mechanical ventilation (MV), length of intensive care unit (ICU) stay, and SBT process, as well as underlying disease, was positively correlated with extubation/weaning failure. While age, gender, vital signs (MAP, RR, and HR), sequential organ failure assessment (SOFA), and acute physiology and chronic health evaluation (APACHE) scores had no significant correlation with patients' extubation outcomes. Conclusion According to our findings, integrating CVP assessment into SBT besides routine indices measurement and monitoring can be considered for the prediction of weaning outcome in critically ill mechanically ventilated patients.


| INTRODUCTION
In routine clinical practice, weaning is accomplished using a standardized process known as spontaneous breathing trial (SBT), which involves a real-life test of breathing without mechanical ventilation performed before extubation to validate the patient's capacity to breathe without support. SBT estimates the risk of unsuccessful weaning by analyzing the physiological responses to the respiratory effort induced by the cessation of positive pressure breathing during a 30-120-min period. 1,2 Even though SBT can cause complications for some patients, such as increased cardiovascular and physical stress, impaired cardiac function, arrhythmia, or ischemia, so switching from mechanical to spontaneous ventilation can reduce left ventricular function by raising preload and afterload and uncovering latent left ventricular failure. 3 Additionally, as evidenced by recent studies, SBT failure might lead to greater muscular effort and fatigue, indicating that SBT can pose risks and complications for the patient. 4 As a result, it is essential to investigate potential factors that are not included in routine SBT and identify individuals at high risk of unsuccessful extubation before or even during the early minutes of SBT that have not yet posed complications to the patient. 5 Unsuccessful extubation with emergency re-intubation is a serious consequence of the failed weaning process, which leads to enhanced mortality. 6 Cardiovascular dysfunction is being recognized as a frequent cause of weaning failure that can be successfully treated. Clinically, it may be challenging to diagnose and distinguish cardiovascular pathophysiology as a primary risk factor or contributor to weaning failure from noncardiac causes, demanding high suspicion for its early diagnosis and intervention. 7 Switching a patient from positive pressure ventilation to spontaneous breathing restores negative inspiratory intrathoracic pressures, increasing venous return (left ventricular preload), central blood volume, and left ventricular afterload. It is best addressed before weaning tests since it is associated with a poor prognosis for extubation/weaning. 8 A recent study found that evaluating volume status and response to the volume before SBT is associated with a higher risk of pulmonary edema induced by weaning, 9 thus, monitoring volume status before isolation is not practicable in all patients. Furthermore, in cases of unsuccessful extubation with the cardiovascular origin, a simultaneous rise in pulmonary artery occlusion pressure and central venous pressure (CVP) has been demonstrated. 10 Given the above reflection, we aimed to investigate the predictive factors of the weaning outcome before and during SBT in mechanically ventilated patients, with the hypothesis that an early rise in CVP during SBT might be a signal of heart failure and unsuccessful extubation/weaning.

| Study design
This cross-sectional study was carried out on critically ill patients undergoing mechanical ventilation who had been hospitalized for more than 48 h in the ICUs of Shohada and Imam Reza hospitals (two university-affiliated hospitals in the northwest of Iran). The protocol of this study was reviewed and approved by the Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1399.364), and all participants or their next of kins were fully informed of the information and provided written consent.

| Study subjects
We recruited 159 patients based on the following inclusion and exclusion criteria. The main criterion for inclusion in this study was that the patient met the clinical criteria for weaning or SBT.

| Weaning trial
Patients who were eligible for SBT were ventilated with pressure support ventilation (PSV) and PEEP before the procedure, as per the department's protocol (PSV = 6-8 cmH 2 O and PEEP: 5-6 cmH 2 O).
SBT was performed with a T tube connected to oxygen while the patient was supine and at 30°, with no change in the patient's position during SBT. The co-executor of the protocol determined the duration of the T tube at 120 min, and if tolerated, the patient was prepared for extubation. If the patient exhibited signs of intolerance during this period, SBT was discontinued and the patient was returned to PSV. Clinical criteria used to determine whether SBT was successful were a respiratory rate (RR) <35, less than a 20% rise over baseline heart rate (HR), oxygen saturation (SpO 2 ) >90%, any change less than 25% in blood pressure, and the absence of signs of increased respiratory work or respiratory distress (contraction of lateral muscles, paradoxical or asynchronous chest movements, intercostal contractions, diaphoresis, nasal flaring, and agitation).
The decision to extubate a patient after successful SBT and optimal consciousness was made based on the patient's clinical status. If the patient's condition remained stable after extubation for 48 h, the extubation was considered successful, and clinical follow-up was

| CVP test
Among other factors, CVP was measured at the initiation of SBT, 3 min later, and at the end. CVP was measured by a nurse who was blinded to the study, and the measurement was done by one nurse in T A B L E 1 Clinical findings of the studied population. each center to minimize interobserver variability. The CVP measurement method was to first decrease PEEP to 0, and then CVP was measured at the end of exhalation using a CV line inserted into the internal jugular or subclavian vein in the fourth intercostal space at the midaxillary line.

| Statistical analysis
The normal distribution of the data was evaluated using the  During SBT, there was no significant difference in HR, MAP, RR, or PaCO 2 between patients with successful and failed extubation.
However, at the end of SBT, SpO 2 (p < 0.0001) and PaO 2 (p = 0.002) were substantially higher in patients who were successfully extubated compared to their unsuccessful counterparts, but there was no significant difference in their values at baseline and 3 min after SBT initiation. Likewise, in extubation failure patients, the CVP was significantly higher 3 min after SBT started (p < 0.0001) and at the end of SBT (p < 0.0001) compared to patients with successful extubation ( Table 2).

| DISCUSSION
The success or failure of an SBT is determined by objective and subjective criteria, as well as whether it leads to successful extubation or necessitates re-intubation. Given the fact that these criteria and instructions do not include the CVP, our study demonstrated that elevated CVP during SBT is an independent indicator that is positively associated with weaning failure.
CVP is defined as the interaction between the cardiac and venous return curves, which may be influenced by discontinuing positive pressure mechanical ventilation. The normal CVP response during SBT typically declines in patients with normal cardiac function and without fluid overload or strong inspiratory efforts. 11 As a result, the initial increase in CVP may be interpreted as abnormal in the context of SBT. CVP values are significantly influenced by strong respiratory efforts that result in fluctuations in negative pleural pressure. 12 However, since the CVP assessment was accomplished only 3 min after the end of positive pressure ventilation and SBT, it is unlikely that this factor impacted the CVP values clinically. In this way, Dubo and colleagues demonstrated that CVP increased significantly in the early minutes of SBT, but they could not clarify the underlying reasons for the absence of this pattern at the end of SBT. Nonetheless, they highlighted the potential significance of increased CVP as a potent but transient early warning sign that is best acknowledged after the commencement of SBT. 13  intrathoracic pressure from positive to negative pressure. This can lead to a sharp rise in venous return and a simultaneous increase in left ventricular afterload, which is accompanied by an increase in adrenergic tone during SBT. 11,15 In the context of fluid resuscitation, Weil et al. 17 suggested that CVP be employed as a measure of venous return intolerance. Also, in a preliminary study, Lemaire et al. found that pulmonary edema occurred immediately after initiation of spontaneous breathing if CVP increased by 12 mmHg. 9 In another study, Dres et al. 18 found that patients who failed SBT attributable to cardiac dysfunction had a mean rise of 5 mmHg in CVP during SBT, whereas patients with successful weaning had a CVP increase of just 1 mmHg. It is difficult to evaluate cardiac dysfunction during SBT due to the need for echocardiography in patients; one reason for this is the patient's semi-sitting position during SBT and occasionally rapid breathing, as well as constraints in available facilities. Nonetheless, CVP is a significant predictive factor that is currently not included among the conventional SBT evaluation criteria.
However, a rise in CVP should only be considered a warning sign since it does not provide diagnostic clues without further assessment. 13 Rousti et al. 19 demonstrated that weaning failure can be prevented and even reversed in selected individuals by assessing cardiac function and implementing drainage interventions including diuretics and vasodilators. As a result, an abnormal rise in CVP during SBT might signal the need for a rapid assessment of cardiac function in patients and contribute to a more appropriate allocation of limited resources such as echocardiography to patients.
Hb concentration was found to be positively correlated with weaning success in patients with challenging weaning in a large retrospective study by Lai et al. 20 and lower Hb concentration was attributed to extubation failure in a smaller cohort study. 21 Similarly, a prospective case-control study by Georgakas et al. 22 showed that Hb concentration was positively associated with weaning outcome, which was consistent with our findings. The oxygen-carrying capacity of the blood is directly related to the level of Hb, and in normal healthy people, 15 g/dL of Hb carries approximately 21 mL of oxygen per 100 mL of blood. 23,24 In this way, a decline in Hb levels leads to a decrease in oxygen-carrying capacity. Since Hb saturation is commonly abnormal in patients with respiratory failure, this consequence is more prominent. 25 Therefore, the decrease in oxygen-carrying capacity is expected to disrupt the aerobic metabolism of respiratory muscles, culminating in breathing inefficiency and weaning failure.
Also, SpO 2 was identified as an independent predictive factor for weaning success. This finding is consistent with previous studies that an integrated index that includes SpO 2 has higher diagnostic accuracy than other conventional indices in predicting weaning outcomes, 24 and a higher SpO 2 level is positively correlated with SBT success. 22 As arterial oxygen content is low, the blood-to-mitochondria oxygen diffusion gradient diminishes more rapidly, potentially driving respiratory muscles toward primary anaerobic metabolism and resulting in breathing inefficiency and weaning failure. 23 Several research, notably the one by Teixeira and colleagues have indicated that PaO 2 at the initiation and end of SBT cannot be distinguished between two groups with successful and failed weaning. 22,26,27 In contrast, we found that the PaO 2 level at the end of SBT was a factor associated with extubation success, but there was no correlation at baseline or 3 min after the initiation of SBT. Most patients undergoing weaning have substantial gas exchange abnormalities during the weaning process and may become hypoxemic, hypercapnic, or both during SBT. 28 Goodgame et al. 29  Tanios and colleagues previously demonstrated that using predictive cues while deciding whether to perform SBT delays extubation. 31 However, determining the optimal timing for extubation is essential. Early extubation is linked to an increased risk of reintubation, a higher requirement for tracheostomy, a longer ICU stay, and a higher mortality rate. 32 Late extubation, on the other hand, raises the risk of pneumonia, ICU stay, and mortality. 2,33 In this respect, Teixeira et al. 26 found that the length of stay in the ICU and the duration of mechanical ventilation were significantly longer in the group that failed extubation than in the group that succeeded. Based on strong evidence, the task force recommended in 2001 that SBT last at least 30 min and no more than 120 min. 35 This suggests that we should wait at least 30 min before assessing SBT tolerance, but not more than 120 min if SBT tolerance is uncertain.
Before deciding to continue SBT, the first few minutes should be carefully reviewed. There is evidence that respiratory muscle fatigue is detrimental if it develops early with ineffective SBTs. 36 Our study was the first to demonstrate that the duration of the SBT process had a positive correlation with extubation failure.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data sets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

ETHICS STATEMENT
All procedures were carried out with the approval of the

TRANSPARENCY STATEMENT
The lead author Ata Mahmoodpoor affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.